The autoimmune disease process underlying type 1 diabetes (type 1 DM) relies upon interactions between genetic susceptibility genes located both inside and outside of the major histocompatibility complex (MHC) and multiple components of the immune system [i.e., antigen presenting cell (APC), T-cells]. Whereas previous studies have demonstrated that individuals with or at increased-risk of type 1 DM (e.g., autoantibody positive relatives) display a number of immunological abnormalities, the contribution of specific genes to this process as well as an informative description of the interactions between specialized immunoregulatory cell populations remains unclear. Our goal in seeking renewal of this program project grant (PPG) is to continue to elucidate the mechanisms by which type I DM susceptibility genes interact with APC (B-cells, dendritic cells, macrophage/monocytes) and cellular immune system components (T-cells, NK T cells) to engender the autoimmune destruction of pancreatic beta cells. This PPG will examine this important issue through three separate but highly interactive projects: B- Lymphocyte Subsets in Type I Diabetes; PGS2 in the Pathogenesis of Type I DM; Cellular Immunoregulation by DC and Diabetes Progression. The first project will examine the molecular and cellular mechanisms underlying the recent observations revealing a critical role for B-lymphocytes in the formation of type 1 DM and insulitis in NOD mice. With convincing data that NOD mice and humans at increased-risk for type 1 DM display abnormally high levels of prostaglandin synthase- 2 (PGS-2), the second Project will seek to identify a role for this molecule in the pathogenesis of the disorder. The third Project will prospectively monitor a number of cellular immune activities (i.e., blastogenesis/cytokine production to beta cell antigens, analyze DC subsets and APC function, frequency of CD1d-restricted T cells( recently ascribed as being critical to diabetes susceptibility and progression to disease. Both Projects 2 and 3 will involve examination of extremely valuable study populations with type 1 DM or at various levels of risk for the disease including those participating in diabetes prevention trials and studies involving perspective assessment of autoimmunity in newborns. These Projects will be supported by three Core facilities: Mouse Facility; Laboratory. The successful completion of these PPG studies will be beneficial to improving our understanding of events critical to the natural history of progression to type 1 DM, identify genetic/immunologic screening tools for the disease, and potentially, to uncover selective immunotherapies capable of preventing the disorder.